Anacardium occidentale is a tall evergreen tree of Anacardiaceae that originated in Brazil, and yellow pear-shaped stalks thereof, when swollen to a size of 5 to 6 cm, are referred to as “cashew apples.” The cashew apple smells like an apple and it is occasionally processed so as to be consumed fresh or in the form of juice beverage. Fruits covered with husks having the size of 2 to 3 cm and the curved and comma-shaped form are generated at the ends of swollen stalks. Kernels in the husks are cashew nuts. Cashew nuts are extensively used as food all over the world.
The term “anthocyanidin” refers to a type of colored aglycon belonging to the group of flavonoids and obtained via hydrolysis of anthocyanin. Anthocyanidin is roughly classified into three types (i.e., delphinidin, cyanidin, and pelargonidin types) depending on the number of hydroxyl bonds. The term “proanthocyanidin” refers to an ingredient that produces anthocyanidin when heated under acidic conditions, and it is a condensed tannin; i.e., compounds resulting from condensation or polymerization of flavan-3-ol or flavan-3,4-diol, as a constitutional unit. Proanthocyanidin, which generates delphinidin when heated under acidic conditions, is referred to as “prodelphinidin.” Proanthocyanidin, which generates cyanidin, is referred to as “procyanidin,” and proanthocyanidin, which generates pelargonidin, is referred to as “propelargonidin.” Polymers of gallocatechin, epigallocatechin, gallocatechin gallate, and epigallocatechin gallate are known as prodelphinidins, and polymers of catechin, epicatechin, catechin gallate, and epicatechin gallate are known as procyanidins.
The cashew apple is known to contain anacardic acid and the like, although the existence of proanthocyanidin has not been reported.
Patent Document 1 (JP Patent Publication (Kokai) No. H09-291039 A (1997)) discloses an anti-obesity drug comprising, as an active ingredient, 2-mer to 80-mer procyanidin obtained from a tamarind seed coat extract. Patent Document 2 (JP Patent Publication (Kokai) No. 2006-151944 A) describes drugs for regulating neutral fat metabolism containing apple-derived polyphenol, including a procyanidin. Regarding the lipase inhibitory activity of procyanidin, Non-Patent Document 2 (J. Agric. Food Chem. 2007, 55, 4604-4609) describes that apple-derived procyanidins are precisely purified in accordance with degrees of polymerization, and lipase inhibitory activities are examined. In Non-Patent Document 2, the lipase inhibitory activity (IC50) of 9-mer or higher procyanidin was given as 0.9 μg/ml, and that of chlorogenic acid, which was simultaneously measured, was given as 59.8 μg/ml. Alpha-amylase inhibitory activity and lipase inhibitory activity of prodelphinidin polymers are not known.
The following report has been made regarding prodelphinidin polymers. Patent Document 3 (JP Patent Publication (Kokai) No. 2008-138129 A) reports, as an “amylase inhibitor,” an alpha-amylase inhibitor comprising a polymer of catechins selected from the group consisting of epicatechin, epicatechin gallate, epigallocatechin gallate, and epigallocatechin. This polymer was artificially synthesized via an enzyme reaction, and the claims of the above patent document describe that the number average molecular weight thereof is 10,000 or lower and the degree of polymerization is 2 to 20. All the examples describe the results of synthesis of a polymer of epigallocatechin gallate and a polycondensation product of epigallocatechin gallate and aldehyde. It can be inferred based on Patent Document 3 that prodelphinidin which is a polymer of epigallocatechin gallates has alpha-amylase inhibitory activity. However, the polymer described in Patent Document 3 is a compound obtained via an artificial reaction, many structural features remain unknown, and safety thereof when consumed also remains problematic.
Examples of patent documents regarding prodelphinidin include the following. Patent Document 4 (JP Patent Publication (Kokai) No. 2006-16367 A) describes lipase inhibitory activity of prodelphinidin having a plurality of dimers as molecular structures. Patent Document 5 (JP Patent Publication (Kokai) No. 2006-1909 A) describes a novel compound having lipase inhibitory activity. According to these patent documents, the lipase inhibitory activities (IC50) of epigallocatechin gallate ((−)-epigallocatechin 3-O-gallate) are 0.284 μM and 0.349 μM (0.16 μg/ml), respectively. Non-Patent Document 1 (J. Agric. Food Chem, 2003, 51, 7513-7521) describes the results of analysis of constituents of a plurality of plant proanthocyanidins. This document, however, does not describe proanthocyanidins having average degrees of polymerization (mDP) of 50 or greater, and it does not report those comprising epigallocatechin gallate as constituents. While Non-Patent Document 1 teaches that “cashew”, listed as one of nuts, contains proanthocyanidin in the form of an (epi)catechin dimer, the cashew apple is not mentioned.
Examples of patent documents regarding grape-derived proanthocyanidin include the following. Patent Document 6 (JP Patent Publication (Kokai) No. 2000-44472 A) describes that a proanthocyanidin oligomer (2- to 30-mer, preferably 2- to 10-mer) obtained from seeds, seed vessels, or the like of grapes has effects of inhibiting elevation in blood glucose levels and is effective as a therapeutic agent for diabetes as “a preventive or therapeutic agent for diabetic complications.” While Patent Document 6 does not describe amylase inhibitory activity, it reports examples of blood glucose levels of diabetic rats that have been lowered with procyanidin B-3 (a dimer) and proanthocyanidin (a proanthocyanidin oligomer of a grape seed extract). Proanthocyanidin in such grape seed extract is considered to be procyanidin (an (epi) catechin polymer) (see Non-Patent Document 4 (Koushou Kaishi (Journal of Japanese Cosmetic Science Society), Vol. 27, No. 4, 2003) and Non-Patent Document 1 (J. Agric. Food Chem., 2003, 51, 7513-7521)).
A variety of active ingredients are known as lipase inhibitors.
Patent Document 7 (JP Patent Publication (Kokai) No. 2008-19180 A) describes the results of experimentation in which the lipase inhibitory activity of a Bergenia ciliata extract was compared with ibuprofenpiconol and tetracycline hydrochloride as positive controls.
Patent Document 8 (JP Patent Publication (Kokai) No. 2005-53891 A) discloses an invention intended to provide a lipase inhibitor having excellent pancreatic lipase or bacterial lipase inhibitory effects, contained in many plant species, excellent in safety, and effective when used for a tendency for obesity, pimples, or dermatitis. The examples of Patent Document 8 describe that caffeic acid (caffeine acid or 3,4-dihydroxycinnamic acid), gallic acid, and rosmarinic acid are effective as lipase inhibitors, and the examples also provide measured values thereof.
Patent Document 9 (JP Patent Publication (Kokai) No. 2004-115466 A) discloses an external skin preparation having effects of preventing and treating pimples containing proanthocyanidin. According to the claims of Patent Document 9, proanthocyanidin is derived from pine bark, grapes, blueberries, strawberries, avocados, false acacia, fruit or seeds of cowberries, barley, wheat, soybeans, black soybeans, cacao, peanut membranes, or Ginkgo biloba leaves. The examples do not describe lipase inhibitory activity, but the examples describe the results of an experiment regarding minimal growth inhibition of Propionibacterium acnes using a pine bark extract.
Patent Document 10 (JP Patent No. 3966689 B) describes a skin-disease-ameliorating agent for pimples containing an extract of rose root (Rhodiola rosea) and/or golden root (Rhodiola sacra) belonging to Crassulaceae. In the examples of Patent Document 10, a plurality of plant extracts are examined regarding lipase inhibitory activity derived from bovine pancreas. Among such plant extracts, patents have been granted for rose root and golden root extracts having lipase inhibitory activity (IC50) of 40 μg/ml.
Pimples are developed mainly on the faces of adolescent boys and girls. The increased sebum secretion, inflammation caused by fatty acid generated by lipase of the epidermis or Propionibacterium acnes, abnormal multiplication of Propionibacterium acnes, and the like are considered to be the causes thereof. Prevention and treatment of pimples have heretofore involved the use of antibacterial agents (e.g., Patent Documents 11 and 12). However, such prevention and treatment techniques disadvantageously involve side effects caused by an antibacterial agent, development of bacteria resistant to an antibacterial agent, excessive disinfection of resident microbiota of the skin by an antibacterial agent, and other problems. Accordingly, development of highly safe pharmaceutical preparations capable of inhibiting excessive growth of Propionibacterium acnes has been awaited.    [Patent Document 1] JP Patent Publication (Kokai) No. H09-291039 A (1997)    [Patent Document 2] JP Patent Publication (Kokai) No. 2006-151944 A    [Patent Document 3] JP Patent Publication (Kokai) No. 2008-138129 A    [Patent Document 4] JP Patent Publication (Kokai) No. 2006-16367 A    [Patent Document 5] JP Patent Publication (Kokai) No. 2006-1909 A    [Patent Document 6] JP Patent Publication (Kokai) No. 2000-44472 A    [Patent Document 7] JP Patent Publication (Kokai) No. 2008-19180 A    [Patent Document 8] JP Patent Publication (Kokai) No. 2005-53891 A    [Patent Document 9] JP Patent Publication (Kokai) No. 2004-115466 A    [Patent Document 10] JP Patent No. 3966689 B    [Patent Document 11] JP Patent Publication (Kokai) No. 2004-189656 A    [Patent Document 12] JP Patent Publication (Kokai) No. 2006-213633 A    [Non-Patent Document 1] J. Agric. Food Chem, 2003, 51, 7513-7521    [Non-Patent Document 2] J. Agric. Food Chem. 2007, 55, 4604-4609    [Non-Patent Document 3] J. Agric. Food Chem., 2002, 50, 4852-4860    [Non-Patent Document 4] Koushou Kaishi (Journal of Japanese Cosmetic Science Society), Vol. 27, No. 4, 2003